A review of the literature has shown that immunohistochemical staining with mAb to monomorphic determinants of HLA Class I antigens has not detected HLA Class I antigens in about 20% of 275 primary lesions and in about 40% of 355 metastatic lesions. These abnormalities are associated with a poor clinical course of the disease. Furthermore, they may have a negative impact on the efficacy of active specific immunotherapy, since they provide melanoma cells with a mechanism to escape from destruction by HLA Class I restricted cytotoxic T cells recognizing melanoma associated antigens (MAA). Recent studies with a limited number of melanoma lesions have found a selective loss of HLA Class I allospecificities in melanoma lesions without detectable abnormalities in the staining by mAb to monomorphic determinants.- Therefore,-it is our-working hypothesis that the- frequency of abnormalities -in-HLA Class -I antigen expression in melanoma lesions is higher than that reported in the literature, since the published studies performed with mAb to monomorphic determinants of HLA Class I antigens have not detected selective losses of HLA Class I allospecificities. Furthermore, it is our working hypothesis that selective loss of HLA Class I allospecificities may account for resistance to lysis by cytotoxic T cells recognizing MAA of melanoma cells without detectable abnormalities in the reactivity with mAb to monomorpnic determinants of HLA Class I antigens, since the lost HLA Class I allospecificity is the immunodominant restricting element. Lastly, it is our working hypothesis that resistance to lysis by autologous cytotoxic T cells because of selective loss of a HLA Class I allospecificity may account for i) poor prognosis in patients without detectable abnormalities in the reactivity of their melanoma lesions with mAb to monomorphic determinants of HLA Class I antigens and ii) lack of efficacy of active specific immunotherapy with peptides presented in the context of the lost HLA Class I allospecificity. The goal of this application is i) to investigate the frequency of the selective loss of HLA Class I allospecificities in melanoma lesions ii) to assess the role of selective loss of HLA Class I allospecificities in the resistance of melanoma cells to lysis by autologous cytotoxic T cells recognizing MAA and in the clinical course of the disease, and iii) to characterize the molecular mechanisms underlying the selective loss of HLA Class I allospecificities. The information resulting from the outlined studies will be utilized to design the strategy to screen melanoma lesions for selective loss of HLA Class I allospecificities and to develop approaches to correct these abnormalities.